Obesity as defined by a body mass index (BMI) >30 kg/m now affects 31% of adults in the United States and results in increased risk for breast cancer. Biologic mechanisms to explain the association between breast cancer and postmenopausal obesity include elevated levels of breast tissue mitogens including bioavailable estrogen and androgens. Excess body weight and fat are also associated with an increase in inflammatory cytokines which further increase proliferation and inhibit apoptosis. Reversible established risk biomarkers for postmenopausal breast cancer include tissue evidence of proliferative breast disease (hyperplasia or atypical hyperplasia) and associated molecular markers (e.g., proliferation), serum bioavailable estradiol and testosterone, mammographic breast density and BMI. Intervention effect biomarkers provide an estimate of the physiologic response to the intervention based on the presumed mechanism of action. For diet and exercise, biomarkers would include fasting glucose and insulin levels, and inflammatory markers such as C reactive protein, in addition to changes in weight, percent body fat, and BMI. We hypothesize that favorable modulation of biomarkers associated with weight loss and exercise will be correlated with favorable modulation in breast cancer risk biomarkers, which will ultimately be associated with a reduction in breast cancer. As a first step in addressing this hypothesis, it is necessary to assess feasibility and to .determine in a preliminary fashion whether the intervention is having the desired effect on risk biomarkers. Our goal is to induce at least a 5% weight loss using a six-month intensive diet/ exercise/behavioral modification intervention developed and tested by Donnelly and colleagues and proven to result in high adherence and significant weight loss in the majority of overweight postmenopausal women. The primary response biomarker assessed will be modulation of proliferation in benign hyperplastic epithelium using the technique of random periareolar fine needle aspirations (RPFNA) for tissue acquisition and assessment developed by Fabian and colleagues. The expertise of these two groups of investigators will be combined in this novel translational pilot study. Specific Aim 1: To determine if a 5% or greater weight loss in overweight high risk postmenopausal women is correlated with favorable modulation of risk factors for breast cancer (Ki-67 in hyperplastic foci, cytomorphology, breast density, serum bioavailable estradiol and testosterone, and SHBG). Specific Aim 2: To determine if change in intervention effect biomarkers (fasting glucose, insulin, and C- reactive protein) correlate with change in breast cancer risk biomarkers. The results of this study will potentially lead to a larger controlled trial to document the beneficial effects of exercise/diet/behavioral modification on risk factors for breast cancer development and all cause mortality. [unreadable] [unreadable] [unreadable]